HIV-1 Infection Leads to Increased Transcription of Human Endogenous Retrovirus HERV-K (HML-2) Proviruses In Vivo but Not to Increased Virion Production
HIV-1 Infection Leads to Increased Transcription of Human Endogenous Retrovirus HERV-K (HML-2) Proviruses In Vivo but Not to Increased Virion Production
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DOI：
10.1128/jvi.01623-14
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发表时间：
2014-10-01
影响因子：
5.4
通讯作者：
Coffin, John M.
中科院分区：
文献类型：
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作者：
Bhardwaj, Neeru;Maldarelli, Frank;Coffin, John M.
最近的研究表明，人类内源性逆转录病毒K组（HERV-K）前病毒的表达在HIV-1感染的发病机制中起作用。特别是，来自HERV-K前病毒的HML-2亚组的RNA已被报道在细胞水平高度表达，并且在HIV-1感染患者的血浆中可检测到，这表明病毒体产生，并且可能是复制。在这项研究中，我们开发了一种HML-2特异性定量PCR检测方法，可检测人类基因组中89种已知HML-2前病毒中的51种。收集HIV阴性对照和HIV-1感染患者的血浆和外周血单核细胞（PBMC）用于分析HML-2 RNA表达。与以前的报道相反，我们没有在HIV-1感染患者的血浆中检测到高水平的HML-2 RNA，但我们确实观察到与HIV阴性对照相比，总PBMC中的HML-2 RNA显著增加。PBMC中HML-2的表达水平似乎与患者使用抗逆转录病毒药物或HIV-1血浆RNA、细胞RNA或细胞DNA水平无关。为了研究HML-2 RNA表达的来源，将患者PBMC分选为CD 3（+）CD 4（+）、CD 3（+）CD 8（+）、CD 3（+）CD 14（+）和CD 3（+）CD 20（+）细胞亚群，然后分析HML-2 RNA水平。在HIV-1感染的患者中没有单一细胞亚群富集HML-2 RNA表达，但HML-2表达水平似乎存在很大的变异性，这取决于细胞类型。我们报道了人类内源性逆转录病毒K组（HERV-K）（HML-2）前病毒在HIV患者的外周血单核细胞（PBMC）中以显著更高的水平表达。1感染比那些未感染的人。然而，与以前的报道相反，这种表达并没有导致在这些患者的血浆中检测到病毒粒子。此外，我们发现HML-2前病毒在HIV-1感染者的多种血细胞类型中表达，并且HML-2表达的幅度与该患者队列中的HIV-1疾病标志物无关。这些发现可能对基于HML-2的靶向HIV-1感染的治疗有意义。
Recent studies suggest that human endogenous retrovirus group K (HERV-K) provirus expression plays a role in the pathogenesis of HIV-1 infection. In particular, RNA from the HML-2 subgroup of HERV-K proviruses has been reported to be highly expressed at the cellular level and detectable in the plasma of HIV-1-infected patients, suggestive of virion production and, perhaps, replication. In this study, we developed an HML-2-specific quantitative-PCR assay that detects 51 of the 89 known HML-2 proviruses in the human genome. Plasma and peripheral blood mononuclear cells (PBMCs) from HIV-negative controls and HIV-1-infected patients were collected for analysis of HML-2 RNA expression. Contrary to previous reports, we did not detect high levels of HML-2 RNA in the plasma of HIV-1-infected patients, but we did observe a significant increase of HML-2 RNA in total PBMCs compared to HIV-negative controls. The level of HML-2 expression in PBMCs does not appear to be related to patient use of antiretrovirals or to HIV-1 plasma RNA, cellular RNA, or cellular DNA levels. To investigate the source of HML-2 RNA expression, patient PBMCs were sorted into CD3(+) CD4(+), CD3(+) CD8(+), CD3(+) CD14(+), and CD3(+) CD20(+) cell subsets and then analyzed for HML-2 RNA levels. No single cell subset was enriched for HML-2 RNA expression in HIV-1-infected patients, but there appears to be substantial variability in the level of HML-2 expression depending on the cell type.IMPORTANCEHere, we report that human endogenous retrovirus group K (HERV-K) (HML-2) proviruses are expressed at significantly higher levels in peripheral blood mononuclear cells (PBMCs) from patients with HIV-1 infection than in those from uninfected individuals. However, contrary to previous reports, this expression did not lead to detectable virions in the plasma of these patients. In addition, we found that HML-2 proviruses were expressed in multiple blood cell types from HIV-1-infected individuals, and the magnitude of HML-2 expression was not related to HIV-1 disease markers in this patient cohort. These findings may have implications for HML-2-based therapies targeting HIV-1 infection.